Thyroid hormones reduce cholesterol and have been proposed to function as a hormonal and nutritional therapy for hypercholesterolemia. T3 is the thyroid hormone that is most active as a ligand for thyroid nuclear receptors. In contrast, the metabolic effects of T2, a form of thyroid found in foods, are involved non-thyroid receptor processes. Unlike thyromimetics, we have found that T2 effectively lowers cholesterol in LDL receptor knockout mice. This provides us with a system to explore non-LDL receptor pathways regulating plasma apoB levels. In Aim 1, we propose to study lipoprotein kinetics, gene and protein expression in wild type and LDL receptor knockout mice treated with T2, and for comparison T3. Aim 2 will use genetically modified mice to determine whether addition of T2 and T3 require these gene products to reduce cholesterol or for increased cholesterol in the setting of hypothyroidism. The significance of the experiments is that our studies will define a non-LDL receptor dependent process for cholesterol reduction that could illustrate a therapeutic target useful as an addition to statins, in statin intolerance, and in patients with homozygous LDL receptor deficiency. PUBLIC HEALTH RELEVANCE: High plasma cholesterol level is an important public health problem in the United States. Although statin is an effective cholesterol-lowering drug, about 1-5% of patients experience statin intolerance and it is ineffective in patients homozygous for mutations in LDL receptors. We propose to use T2, a form of thyroid hormones found in foods, as a tool to study how it lowers plasma cholesterol levels in the absence of LDL receptor. Our studies will define a non- LDL receptor dependent process for cholesterol reduction that could illustrate a therapeutic target alternative to statin therapy.